AUTHOR INFORMATION

Section 1 of 12

Authored by Olufunmilayo Ogundele, MD, Clinical Assistant Instructor, Staff Physician, Departments of Emergency and Internal Medicine, State University of New York Downstate, Kings County Hospital Center

Coauthored by Mark A Silverberg, MD, FACEP, MMB, Assistant Professor of Emergency Medicine, State University of New York Downstate College of Medicine, Assistant Residency Director, Department of Emergency Medicine, Kings County Hospital; James Foster, MD, MS, Consulting Staff, Department of Emergency Medicine, Palomar Pomerado Health

Olufunmilayo Ogundele, MD, is a member of the following medical societies: American Medical Association, and Society for Academic Emergency Medicine

Edited by Debra Slapper, MD, Consulting Staff, Department of Emergency Medicine, St Anthony's Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Mark W Fourre, MD, Program Director, Department of Emergency Medicine, Maine Medical Center, Associate Clinical Professor, Department of Surgery, University of Vermont School of Medicine; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Steven C Dronen, MD, FAAEM, Director of Emergency Services, Director of Chest Pain Center, Department of Emergency Medicine, Ft Sanders Sevier Medical Center

Author's Email:	Olufunmilayo Ogundele, MD
Editor's Email:	Debra Slapper, MD

eMedicine Journal, June 19 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 12

Background: Erythema multiforme (EM) was initially described in 1866 by Ferdinand von Hebra as an acute self-limited skin disease, symmetrically distributed on the extremities with typical and often recurrent concentric "target" lesions. The term EM minor was proposed later to differentiate the mild cutaneous syndrome from the more severe form, EM major, which involves several mucous membranes.

Stevens-Johnson syndrome (SJS) was considered an extreme variant of EM for many years, while toxic epidermal necrolysis (TEN) was considered a different entity. However, in 1993, a group of medical experts proposed a consensus definition and classification of EM, SJS, and TEN based on a photographic atlas and extent of body surface area involvement. According to the consensus definition, SJS was separated from the EM spectrum and added to TEN. Essentially SJS and TEN are considered severity variants of a single entity. The two spectra are now divided into (1) EM consisting of erythema minor and major (EMM) and (2) SJS/TEN. The clinical descriptions are as follows:

• EM minor - Typical targets or raised, edematous papules distributed acrally

• EM major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).

• SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for SJS and 30% or more for TEN.

Pathophysiology: Pathophysiology of EM is not completely understood but appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.

A recent international prospective study showed that the major cause of EM is herpes virus. It appeared to play a smaller role in SJS/TEN. In fact, recent or recurrent herpes was the principle risk factor for EMM. Drugs were found to be a more common trigger for SJS/TEN.

Histopathologic characteristics include a lymphocytic infiltrate at the dermal-epidermal junction and around dermal blood vessels, dermal edema, epidermal keratinocyte necrosis, and subepidermal bullae formation. Histology and immunochemistry studies have shown that inflammatory infiltrates of EM and SJS/TEN are strikingly different in density and nature. EM has a high density of cell infiltrate rich in T-lymphocytes. By contrast, SJS/TEN is characterized by a cell-poor infiltrate of macrophages and dendrocytes with strong TNF-alpha immunoreactivity. Immune complex deposition is variable and nonspecific. In severe cases, fibrinoid necrosis can occur in the stomach, spleen, trachea, and bronchi.

Frequency:

• In the US: The true incidence of EM is unknown, but it has been estimated to be between 0.01 and 1%. Incidence of SJS and TEN are better characterized and estimated at 0.4-1.2 and 1.2-6 per million person-years, respectively.

• Internationally: Similar to US incidence

Mortality/Morbidity:

• EM not usually associated with any mortality. Most cases are self-limited and resolve without sequelae in 2-4 weeks.

• SJS has a mortality around 5%.

• TEN has a mortality approximately 30%.

Sex: EM affects males more often than females, with a male-to-female ratio ranging from 3:2 to 2:1. Incidence of SJS and TEN are equal in males and females.

Age: All ages are affected, with a peak incidence in the second through fourth decades of life, 20% occur in children and adolescents. This condition is rare in persons younger than 3 years and older than 50 years. EM occurs more in younger patients, while SJS and TEN occur more in older persons.

CLINICAL

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History: In addition to characterizing skin and mucous membrane lesions of EM, a complete history should document recent constitutional symptoms, prior history of herpes simplex infection, and use of prescription and over-the-counter medications.

• Erythema multiforme

• Sudden onset of rapidly progressive, symmetrical, and cutaneous and/or mucocutaneous lesions, with concentric color changes in some or all lesions

• Centripetal spread

• Burning sensation in affected areas

• Pruritus generally absent

• Nonspecific prodromal symptoms suggestive of a viral syndrome in at least 50% of cases, usually 1-14 days before skin lesions develop. Symptoms may include fever, malaise, myalgias, arthralgias, headache, sore throat, cough, nausea, vomiting, and diarrhea.

• SJS/TEN

• Generalized cutaneous and/or mucocutaneous lesions with blisters

• May include symptoms of fever, malaise, myalgias, arthralgias, headache, sore throat, cough, nausea, vomiting, and diarrhea

• Oral pain, which may be severe enough to result in difficulty eating, drinking, or opening the mouth

• Eye pain, edema, and drainage

• Breathing difficulty resulting from tracheobronchial involvement

• Dysuria

Physical:

• Erythema multiforme

• Symmetrically distributed, erythematous, expanding macules or papules evolve into classic iris or target lesions, with bright red borders and central petechiae, vesicles, or purpura.

• Lesions may coalesce and become generalized.

• Vesiculobullous lesions develop within preexisting macules, papules, or wheals.

• Rash favors palms and soles, dorsum of the hands, and extensor surfaces of extremities and face.

• Postinflammatory hyperpigmentation or hypopigmentation may occur.

• Eye involvement occurs in 10% of EM cases, mostly bilateral purulent conjunctivitis with increased lacrimation.

• Mucous membrane blistering occurs in about 25% of cases of EM, is usually mild, and typically involves the oral cavity.

• SJS/TEN

• Fever is common.

• Skin findings may be similar to EM but often are more variable and severe. Inflammatory vesiculobullous lesions, often with hemorrhage and necrosis, are typical. Fixed macules and target lesions may be larger and more confluent than in EM.

• Facial edema or central facial involvement

• Mucous membranes are strongly affected, most commonly mouth, lips, and bulbar conjunctivae; less often, anogenital mucosae are affected. Lips may be edematous, bloody, or crusted. A minimum of 2 mucosal surfaces must be involved; 3 mucosal surfaces are involved in about 40% of cases.

• Blisters or epidermal detachment less than 10% BSA for SJS and more than 30% for TEN; the outer layer of the epidermis separates readily from the basal layer with lateral pressure (positive Nikolsky sign).

• Bullae and shallow ulcers resembling aphthous ulcers are common. When bullae rupture, mucosal lesions become deeply erythematous erosions, often covered by gray pseudomembranous exudates.

• Salivation often is increased.

• Nasopharynx, respiratory tract, GI tract, and genitourinary (GU) tract are sometimes affected.

• Genital involvement consists of hemorrhagic, bullous inflammation; urinary retention and phimosis may occur.

• Eye involvement occurs in approximately 85% of cases. These range from hyperemia to extensive pseudomembrane formation. Synechiae between eyelid and conjunctiva often occurs. Keratitis and corneal erosions are less frequent.

Causes: Approximately 50% of cases are idiopathic, with no precipitating factor identified. Many potential triggers have been implicated as possible causes of EM, SJS, and TEN. Most notably causes are infectious agents and drugs. All 3 disorders are linked to drugs with TEN being exclusively attributed to this factor. Infectious causes are more common in children and are implicated more commonly in EM. Herpes simplex infection is the most common cause in young adults and is strongly associated with recurrent EM. The most prevalent bacterial precipitant is Mycoplasma pneumoniae.

• Viral
  • Herpes simplex I & II

  • Adenovirus

  • Coxsackievirus B5

  • Echoviruses

  • Enteroviruses

  • Epstein-Barr

  • Hepatitis A

  • Hepatitis B

  • Measles

  • Vaccinia

  • Varicella

  • Influenza

  • Mumps

  • Poliovirus

• Bacterial
  • Mycoplasma pneumoniae

  • Proteus species

  • Salmonella species

  • Tuberculosis

  • Vibrio parahaemolyticus

  • Psittacosis

  • Catscratch disease

  • Brucella species

  • Tularemia

  • Gonorrhea

  • Typhoid fever

  • Diphtheria

  • Lymphogranuloma venereum

  • Cholera

  • Yersinia enterocolitica

• Fungal
  • Histoplasmosis

  • Coccidioides species

• Postvaccination
  • Bacille Calmette-Guérin (BCG)

  • Oral polio vaccine

  • Vaccinia

  • Tetanus/diphtheria

• Drugs

• Sulfonamides, including hypoglycemics

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Anticonvulsants

• Barbiturates

• Antituberculous drugs

• Antibiotics

• Pyrazolones

• Phenylbutazone, oxyphenbutazone, and phenazone

• Salicylates

• Malignancy

• Hormonal

• Collagen vascular disease

• Immunologic disorders (sarcoidosis, vasculitides, transient selective C4 deficiency)

• Physical/mechanical factors (tattooing, radiotherapy, cold, sunlight, contactants)

• Risk factors
  • Previous history of EM

  • Male sex

• Herpes simplex infection

DIFFERENTIALS

Section 4 of 12

Herpes Simplex
Pityriasis Rosea
Stevens-Johnson Syndrome
Urticaria

Other Problems to be Considered:

Behçet syndrome
Collagen vascular diseases
Dermatitis herpetiformis
Drug eruptions
Figurate erythema
Fixed drug eruption
Granuloma annulare
Herpes gestationis
Herpetic gingivostomatitis
Lichen planus
Meningococcemia
Mucocutaneous lymph node syndrome
Necrotizing vasculitis
Pemphigoid
Pemphigus vulgaris
Recurrent aphthous ulcers
Secondary syphilis
Septicemia
Serum sickness
Stevens-Johnson syndrome and toxic epidermal necrolysis
Urticaria
Viral exanthems

WORKUP

Section 5 of 12

Lab Studies:

• No specific laboratory tests are indicated to make the diagnosis, which should be arrived at clinically.

• Clinical picture can guide laboratory testing in severe cases.

• CBC usually reveals moderate leukocytosis with atypical lymphocytes. Eosinophil count greater than 1000/mm³ may also be seen. Severely elevated total white blood cell counts indicate infection. Mild anemia may be present.

• Electrolytes values may be abnormal with severe skin and mucous membrane involvement due to fluid losses. These values are useful to guide volume and electrolyte replacement therapy.

• BUN and creatinine tests are indicated to screen for renal involvement and dehydration in severe cases requiring hospitalization.

• Liver function tests may be abnormal with hepatic involvement.

• The sedimentation rate may be elevated but is nonspecific.

• Cultures are indicated in severe cases and should be obtained from blood, sputum, and mucosal lesions.

• HSV antigens can be detected in keratinocytes by immunofluorescence.

• HSV DNA has been detected primarily within keratinocytes by polymerase chain reaction.

Imaging Studies:

• No specific imaging studies are necessary in most cases.

• Chest x-ray may be useful in cases with respiratory symptoms or signs, particularly if an underlying pulmonary infection is suspected.

Procedures:

• Skin biopsy may be performed in equivocal cases, particularly in absence of target lesions.

• Pathological findings include a predominantly inflammatory pattern characterized by high density lichenoid infiltrate rich in T cells, and epidermal necrosis of the basal layer.

TREATMENT

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Prehospital Care: In severe cases, prehospital personnel may need to treat respiratory complications and fluid imbalances aggressively, in the same manner as thermal burns.

Emergency Department Care: Mild cases of EM require only symptomatic treatment, which may include analgesics or NSAIDs; cold compresses with saline or Burow solution; topical steroids; and soothing oral treatments such as saline gargles, viscous lidocaine, and diphenhydramine elixir. SJS and TEN can be life threatening and should be treated in a manner similar to thermal burns.

• Aggressive monitoring and replacement of fluids and electrolytes are of paramount importance.

• Provide supportive respiratory care, including suctioning and postural drainage, as needed.

• Administer empiric antibiotics if clinical evidence of secondary infection exists. Most authorities advise against routine use of prophylactic antibiotics.

• Use analgesics as needed to control pain, which may be severe.

• Avoid systemic corticosteroids in minor cases. In severe cases, their use is controversial because they do not improve prognosis and may increase risk of complications.

• General measures

• Treatment of underlying cause

• Prompt withdrawal of possibly causative drugs. Studies have shown that prompt withdrawal of causative drugs will reduce risk of death by about 30% per day.

• Symptomatic treatment for mild cases

• For more severe cases, meticulous wound care and use of Burow or Domeboro solution dressings may be necessary.

• Oral lesions: Oral rinsing with warm saline or a solution of diphenhydramine, Xylocaine, and Kaopectate for symptomatic relief.

Consultations:

• A dermatologist may be helpful with diagnosis, performance of skin biopsies if indicated, and assistance with care of admitted patients.

• Ophthalmology consultation should be obtained whenever the eyes are involved.

• Internists, critical care specialists, or pediatricians as needed for admitted patients.

MEDICATION

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Steroid use is controversial. Patients who have herpes-induced EM may benefit from acyclovir.

Drug Category: Antivirals -- The goal in use of antivirals is to shorten clinical course, prevent complications, prevent development of latency and/or subsequent recurrences, decrease transmission, and eliminate established latency.

Drug Name	Acyclovir (Zovirax) -- Reduces duration of symptomatic lesions. Indicated for patients presenting within 48 h of experiencing the rash. Patients on acyclovir experience less pain and faster resolution of cutaneous lesions. Acyclovir demonstrates inhibitory activity directed against both HSV-1 and HSV-2; infected cells selectively take it up.
Adult Dose	600-800 mg PO bid for 7-10 d; initiate immediately upon the onset of symptoms of recurrent episodes
Pediatric Dose	10 mg/kg or 500 mg/m2 IV q8h
Contraindications	Documented hypersensitivity
Interactions	Concomitant use of probenecid or zidovudine prolongs half-life; may increase CNS toxicity of acyclovir
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or when other nephrotoxic drugs are coadministered

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Hospitalization for fluid and electrolyte management is indicated when severe mucous membrane involvement is present or with impaired oral intake, dehydration, or secondary infection.

• Implement barrier isolation to decrease risk of infection.

• IV antibiotics may be necessary to treat secondary infections.

• Areas of denuded skin should be managed like thermal burns, although debridement is best avoided while lesions are still progressing.

• Eroded areas may be bathed q1-2d with saline or Burow solution and dressed with nonadherent dressings.

Further Outpatient Care:

• Provide symptomatic relief.

• Discontinue use of potentially contributing drugs.

In/Out Patient Meds:

• Avoid use of systemic corticosteroids in EM; their use is controversial in EMM and SJS/TEN.

• Topical corticosteroids are useful for outpatient treatment of patients with limited disease.

• Prophylactic oral acyclovir is effective in decreasing frequency and severity of recurrent herpes and herpes-associated EM.

• Consider use when recurrences are more frequent than 5 per year.

• Prophylaxis may be required for 6-12 months or longer.

• If unresponsive, continuous therapy of valacyclovir 500 mg bid has been reported effective.

• Case reports exist of alternative treatments with immunosuppressants such as azathioprine. No well-controlled trials exist to support the beneficial effects of immunosuppressive therapy.

• Human intravenous immunoglobulin has been used in treatment of SJS/TEN. However, these studies were open and uncontrolled trials, which make it difficult to accept IVIG as a standard of therapy for SJS/TEN.

• Alternative treatments of EM include dapsone, antimalarials, cimetidine, and thalidomide.

Transfer:

• Severe cases require treatment in an intensive care unit or burn unit.

Deterrence/Prevention:

• Avoid known or suspected predisposing medications.

• Acyclovir may be helpful in reducing recurrence of EM caused by herpes.

• Tamoxifen may prevent premenstrual EM.

Complications:

• Hypopigmentation or hyperpigmentation

• Scarring

• Dehydration and electrolyte disturbances

• Secondary bacterial infections/sepsis

• Ocular complications, including corneal ulceration, anterior uveitis, panophthalmitis, corneal opacities, symblepharon formation, and blindness

• Esophageal, bronchial, urethral, vaginal, and anal strictures (rare)

• Possible GI hemorrhage, renal failure, and respiratory failure in severe cases

Prognosis:

• Most cases of EM are self-limited, with lesions evolving over 1-2 weeks and subsequently resolving within 2-3 weeks. SJS/TEN may require 3-6 weeks to resolve.

• Scarring is rare but may follow SJS/TEN and is more common after resolution of mucosal lesions. Patients who form keloids may be at higher risk.

• Hypopigmentation or hyperpigmentation may follow resolution of lesions.

• Recurrence is common in EM (up to one third of cases) but is not common in SJS/TEN.

• SJS and TEN may have a fulminant course complicated by severe secondary infection, fluid and electrolyte imbalances, and death in 5% and 30% of cases, respectively.

Patient Education:

• Educate patients in appropriate symptomatic treatment.

• Provide reassurance that disease is self-limited.

• Advise of significant risk of recurrence, especially in EM.

• Emphasize avoidance of any identified etiologic agent.

• For excellent patient education resources, visit eMedicine’s Skin, Hair, and Nails Center. Also, see eMedicine’s patient education article Life-Threatening Skin Rashes.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to diagnose Stevens-Johnson syndrome early in the course may result in a premature discharge of the patient, with subsequent deterioration in patient's condition.

• Patients and parents, when appropriate, should be warned about potential long-term complications.

Special Concerns:

• Pregnancy may contribute to development of EM.

• EM is rare in children younger than 3 years.

• EM is rare in persons older than 50 years.

• EM is more common in younger males, while SJS/TEN occurs equally in the sexes with a predominance in older patients.

TEST QUESTIONS

Section 10 of 12

CME Question 1: An 18-year-old woman presents with a new rash. Which of the following historical observations or physical findings would not favor a diagnosis of erythema multiforme?

A: Pruritus
B: Target lesions
C: Oral mucosal blisters
D: Involvement of the palms and soles
E: Prior history of herpes simplex infection

The correct answer is A: Pruritus is uncommon in erythema multiforme, although some patients complain of a burning sensation.

CME Question 2: Which of the following statements is accurate regarding ocular involvement in erythema multiforme (EM)?

A: Ocular involvement is usually unilateral.
B: Ocular involvement occurs in 70% of cases of EM minor and in 10% of cases of EM major.
C: Ocular involvement often results in permanent blindness.
D: Ocular involvement may include corneal ulceration.
E: None of the above

The correct answer is D: Corneal ulceration is one complication of ocular EM. Other ocular complications may include anterior uveitis, panophthalmitis, corneal opacities, symblepharon formation, and blindness.

Pearl Question 1 (T/F): Herpes simplex infection is the most common cause of recurrent erythema multiforme (EM) in young adults.

The correct answer is True: Herpes simplex infection is the most common cause of recurrent EM in young adults. Infectious causes are more common in children and are implicated more commonly in EM minor. Drugs are the major culprits in adults and in EM major.

Pearl Question 2 (T/F): Yersinia enterocolitica is the most common bacterial trigger for erythema multiforme.

The correct answer is False: Mycoplasma pneumoniae is the most common bacterial trigger for erythema multiforme.

Pearl Question 3 (T/F): Erythema multiforme is more common in summer and winter.

The correct answer is False: Erythema multiforme is more common in the spring and fall.

Pearl Question 4 (T/F): No accepted role for systemic steroids in erythema multiforme minor currently exists.

The correct answer is True: No accepted role for the use of systemic steroids in erythema multiforme minor currently exists. In cases of erythema multiforme major, steroid use is controversial. Topical corticosteroids are useful for outpatient treatment of patients with limited disease.

PICTURES

Section 11 of 12

Caption: Picture 1. Target lesion of erythema multiforme (Image courtesy of Chulabhorn Pruksachatkunakorn, MD)
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Caption: Picture 2. Raised atypical targets and arcuate lesions (Image courtesy of Chulabhorn Pruksachatkunakorn, MD)
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Caption: Picture 3. Hemorrhagic crusts on the lips (Image courtesy of Chulabhorn Pruksachatkunakorn, MD)
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BIBLIOGRAPHY

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